Acute overdosage with antibiotics is rare. In the event of overdosage discontinue medication. Gastric lavage plus appropriate supportive treatment is indicated.
Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.
Acute overdosage with antibiotics is rare. In the event of overdosage discontinue medication. Gastric lavage plus appropriate supportive treatment is indicated.
Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.
In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.
To date no significant acute toxicity has been described in the case of a single oral intake of a multiple of therapeutic doses of doxycycline. In case of overdosage there is, however, a risk of parenchymatous hepatic and renal damage and of pancreatitis.
The usual dose of Tetradox is low when compared with the usual doses for doxycycline when used for antimicrobial therapy. Therefore clinicians should bear in mind that a significant proportion of overdoses are likely to produce blood concentrations of doxycycline within the therapeutic range of antimicrobial treatment, for which there is a large quantity of data supporting the safety of the drug. In these cases observation is recommended. In cases of significant overdosage, doxycycline therapy should be stopped immediately; and symptomatic measures undertaken as required. Intestinal absorption of unabsorbed doxycycline should be minimised by producing non-absorbable chelate complexes by the administration of magnesium or calcium salt containing antacids. Gastric lavage should be considered.
Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.
Not applicable.
None known
Not applicable.
The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline.
| System Organ Class | Common >1/100 to <1/10 | Uncommon >1/1000 to <1/100 | Rare >1/10,000 to <1/1000 | Not known Cannot be estimated from the available data. |
| Infections and infestations | Vaginal infection | Candida Infection | ||
| Blood and lymphatic system disorders | Haemolytic anaemia, neutropenia, thrombocytopenia, eosinophilia | |||
| Immune system disorders | Hypersensitivity (including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, angioedema, exacerbation of systemic lupus erythematosus, pericarditis, serum sickness, Henoch-Schonlein purpura, hypotension, dyspnoea, tachycardia, peripheral oedema and urticaria) | Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) | Jarisch-Herxheimer reaction | |
| Endocrine disorders | Brown-black microscopic discoloration of thyroid glands | |||
| Metabolism and nutrition disorders | Porphyria, decreased appetite | |||
| Nervous system disorders | Headache | Anxiety, benign intracranial hypertension (pseudotumor cerebri)*, fontanelle bulging | ||
| Ear and labyrinth disorders | Tinnitus | |||
| Vascular disorders | Flushing | |||
| Gastrointestinal disorders | Nausea/vomiting | Dyspepsia (Heartburn/gastritis) | Pancreatitis, pseudomembranous colitis, Clostridium difficile colitis, oesophageal ulcer, oesophagitis, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, dysphagia, abdominal pain, diarrhoea, glossitis, stomatitis, tooth discolourationa | |
| Hepatobiliary disorders | Hepatic failure, hepatitis, hepatotoxicity, jaundice, hepatic function abnormal | |||
| Skin and subcutaneous tissue disorders | Photosensitivity reaction, rash including maculopapular and erythematous rashes | Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, photoonycholysis | ||
| Musculoskeletal, connective tissue and bone disorders | Arthralgia, myalgia | |||
| Renal and urinary disorders | Blood urea increased |
* Symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.
a Reversible and superficial discolouration of permanent teeth has been reported with the use of doxycycline.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
The following adverse reactions have been observed in patients receiving tetracyclines, including Tetradox.
Adverse Reactions Table
| System Organ Class | Common > 1/100 to < 1/10 | Uncommon > 1/1000 to < 1/100 | Rare > 1/10000 to < 1/1000 |
| Infections and infestations | Vaginal infection | Candida infection | |
| Blood and lymphatic system disorders | Haemolytic anaemia Neutropenia Thrombocytopaenia Eosinophilia | ||
| Immune system disorders | Anaphylactic Reaction (including angioedema, exacerbation of systemic lupus erythematosus, pericarditis, hypersensitivity, serum sickness Henoch- Schonlein Purpura, hypotension, dyspnoea, tachycardia peripheral oedema and urticaria) | Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) | |
| endocrine disorders | Brown-black microscopic discoloration of thyroid glands | ||
| Metabolism and nutrition disorders | Porphyria, decreased appetite | ||
| Nervous system disorders | Headache | Benign intracranial Hypertension (pseudotumor cerebri)* fontanelle bulging | |
| Ear and labyrinth disorders | Tinnitus | ||
| Vascular disorders | Flushing | ||
| Gastrointestinal disorders | Nausea/vomiting | Dyspepsia (Heartburn/ gastritis) | Pancreatitis, pseudomembranous colitis Clostridium.difficile colitis, oesophageal ulcer, oesophagitis, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, dysphagia, abdominal pain, diarrhoea, glossitis, stomatitis |
| Hepatobiliary disorders | Hepatic failure, hepatitis, hepatotoxicity, jaundice, hepatic function abnormal | ||
| Skin and subcutaneous tissue disorders | Photosensitivity reaction, rash including maculopapular and erythematous rashes | Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, photoonycholysis | |
| Musculoskeletal, connective tissue and bone disorders | Arthralgia, myalgia | ||
| Renal and urinary disorders | Blood urea increased |
* Symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.
Tetracyclines may cause discolouration of teeth and enamel hypoplasia, but usually only after long-term use.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines:
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed.
Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above.
Renal: Rise in BUN has been reported and is apparently dose-related.
Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.
Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline
Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.
The most commonly reported adverse reactions in Phase III trials were headache (26%) and common cold (22%). The following table lists those adverse reactions occurring in four Phase III trials conducted in 213 patients.
| Organ System | Undesirable Effect | Very Common (>1/10) | Common (>1/100, <1/10) | Uncommon (>1/1000,<1/100) | Rare (>1/10000,<1/1000) |
| Infections & Infestations | Infection Periodontal Abscess |
| 4 8 |
|
|
| Respiratory | Common Cold Flu Symptoms Sinusitis Coughing Bronchitis | 47 24
|
18 9 7 |
|
|
| Gastrointestinal | Dyspepsia Diarrhoea Acid Indigestion |
| 13 12 8 |
|
|
| Skin Disorders | Rash |
| 8 |
|
|
| Musculoskeletal | Toothache Joint Pain Back Pain Pain Muscle Pain Gum Pain |
| 14 12 11 8
|
2 1 |
|
| Reproductive | Menstrual Cramps |
| 9 |
|
|
| General | Headache Nausea Tooth Disorder Sore Throat Sinus Headache | 55 |
17 13 11 8 |
|
|
| Injury | Accidental Injury |
| 11 |
|
|
The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline:-
Gastrointestinal: Anorexia, nausea, vomiting, diarrhoea, glossitis, dysphagia, enterocolitis and inflammatory lesions with monilial overgrowth in the anogenital region. Hepatotoxity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Oesophagitis and oesophageal ulceration have been reported, most often in patients administered the hyclate salt in capsule form. Most of these patients took medication just prior to going to bed.
Skin: Maculo papular, erythematous rashes and Stevens-Johnson syndrome. Skin photosensitivity can occur. Exfoliative dermatitis has been reported but is uncommon.
Renal: An apparently dose related increase in blood urea has been reported with tetracyclines.
Blood: Thrombocytopenia, neutropenia, haemolytic anaemia, eosinophilia and porphyria have been reported with tetracyclines.
Hypersensitivity reactions: Exacerbation of systemic lupus erythematosus, anaphylaxis, anaphylactoid purpura, pericarditis, urticaria and angioneurotic oedema.
Musculoskeletal: Arthralgia
Other: Bulging fontanelles in infants and benign intracranial hypertension in adults has been reported with the use of tetracyclines. Treatment should cease if evidence of raised intracranial pressure develops. These conditions disappeared rapidly when the drug was discontinued. Brown-black microscopic discolouration of thyroid tissue has been reported with long-term use of tetracyclines. Thyroid function is normal.
Adverse reactions typical of the tetracycline class of drugs are less likely to occur during medication with Tetradox, due to the reduced dosage and the relatively low serum levels involved. This assertion is supported by several clinical trials which suggest that no significant differences exist with regard to frequency of adverse events between active and placebo groupings. However, the clinician should always be aware of the possibility of adverse events occurring and should monitor patients accordingly.
The following adverse events have been reported during post-marketing:
(Frequency estimate: very common > 1 in 10; common >1 in 100 to <1 in 10; uncommon >1 in 1000 to <1 in 100; rare >1 in 10,000 to <1 in 1000; very rare <1 in 10,000) and not known : cannot be estimated from the available data
Infections
Rare: Vaginal moniliasis, Anogenital moniliasis
Immune system disorders
Rare: Mild allergic reactions
Not known: Jarisch-Herxheimer reaction
Nervous system disorders
Rare: Headache
Very rare: Dizziness
Gastrointestinal disorders
Rare: Nausea, diarrhoea, dyspepsia
Very rare: Abdominal pain, constipation, dry mouth, superficial tooth discolouration
There have been isolated case reports of bloody diarrhoea, colitis and pseudomembranous colitis.
Skin and subcutaneous tissue disorders
Rare: Rash
Very rare: Urticaria, pruritus, skin photosensitivity.
Unknown: Photo-onycholysis.
Musculoskeletal disorders
Very rare: Arthralgia
General disorders
Very rare: Asthenia
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Tel: Freephone 0808 100 3352. Website: www.mhra.gov.uk/yellowcard.
None stated
Not applicable.
The carcinogenic potential of doxycycline has been investigated and no changes indicative of a direct carcinogenic effect were seen. Increases in benign tumours of the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma), which are consistent with a hormonal effect, were observed in treated females. Doxycycline has shown no mutagenic activity and no convincing evidence of clastogenic activity.
Effects on fertility and reproductive performance and on pre- and post-natal toxicity have been assessed in rats over the dose range 50 to 500 mg/kg/day. At 50 mg/kg/day (88 times the human dose) there was a decrease in the straight-line velocity of sperm, but there was no apparent effect on male or female fertility or on sperm morphology. Maternal toxicity at 500 mg/kg/day was shown by noisy breathing, loose faeces, and transient reductions in both body weight gain and food consumption after parturition with a slight increase in the duration of gestation. No maternal toxicity was apparent at or below 100 mg/kg/day and there was no effect on the F1 generation at 50 mg/kg/day during parturition, lactation or post-weaning. Developmental toxicity studies have not been conducted, but doxycycline is known to cross the placenta.
Hyperpigmentation of the thyroid following administration of members of the tetracycline class has been observed in rats, minipigs, dogs and monkeys and thyroid hyperplasia has occurred in rats, dogs, chickens and mice.
The anticipated human dose for doxycycline, 20 mg b.i.d. is equivalent to ~0.5 mg/kg/day for a 70 kg man. At this dose plasma Cmax and AUC0-24 were 780 ng/ml and 10954 ng*h/ml respectively.
Toxicity following repeated oral administration has been evaluated in rats and cynomolgus monkeys. Discolouration of the thyroid was a finding common to rats exposed at 25 mg/kg/day for 13 weeks or 20 mg/kg/day for 26 weeks, and to cynomolgus monkeys at 30 mg/kg/day for 1 year. Cmax and AUC0-24 following a single oral dose of 25 mg/kg were 2.2 and 1.6 times respectively the values recorded in man. Dose-related increases in both the incidence and severity of tubular degeneration/regeneration in the kidney were seen following administration to cynomolgus monkeys for 28 days or 52 weeks. At 5 mg/kg/day, focal lesions were present after 28 days, but no lesions were present in monkeys treated for 52 weeks. Mean plasma Cmax and AUC0-24 values at 28 days in monkeys receiving 5 mg/kg/day were 1235 ng/ml and 11600 ng*h/ml respectively and there was no evidence of accumulation.
In humans the use of tetracyclines during tooth development may cause permanent discolouration of the teeth (yellow-grey-brown). This reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. As for other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.
Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02.
Tetradox is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Tetradox is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.
Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02
Tetradox is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Tetradox is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.
Pharmacotherapeutic group: Tetracyclines
ATC code: J01A A02
The active ingredient of Tetradox, doxycycline, is synthetically derived from oxytetracycline, with a molecular formula of C22H24N2O8-HCl-½ C2H5OH-½ H2O.
Tetradox is an inhibitor of collagenase activity. Studies have shown that at the proposed 20 mg b.i.d. dose level, Tetradox reduces the elevated collagenase activity in the gingival crevicular fluid of patients with chronic adult periodontitis, whilst not demonstrating any clinical evidence of anti-microbial activity.
Susceptibility
The dosage achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 months. This product SHOULD NOT be used for reducing the numbers of, or eliminating, those microorganisms associated with periodontitis.
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of doxycycline, unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml of doxycycline at 2 hours decreasing to 1.45 micrograms/ml at 24 hours. Doxycycline has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.
Absorption
Tetracyclines are readily absorbed and are bound to proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentration and in a biologically active form. Tetradox is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of Tetradox unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk.
Following a 200mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml at 2hours decreasing to 1.45micrograms/ml at 24 hours. Tetradox has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Tetradox will not degrade into an epianhydro form.
AbsorptionFollowing administration of a single dose of Tetradox MPC under fasting conditions, the AUCinf and Cmax were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, Tetradox MPC 120 mg Tablets were found to be bioequivalent to Tetradox 100 mg Tablets. When a single dose of Tetradox MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the Cmax was approximately 30% lower, but there was no significant difference in the AUCinf compared to administration under fasting conditions.
ExcretionTetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.
Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.
Absorption:
Doxycycline is almost completely absorbed after oral administration. Following ingestion of 20 mg doxycycline twice daily, mean maximum plasma concentrations were 0.79 µg/ml. Peak levels were generally achieved 2 hours after administration. Food intake reduced the extent of absorption by 10% and decreased and delayed the peak plasma levels.
Distribution:
Doxycycline is greater than 90% bound to plasma proteins and has an apparent volume of distribution of 50L.
Metabolism:
Major metabolic pathways of doxycycline have not been identified, however, enzyme inducers decrease the half-life of doxycycline.
Elimination:
Doxycycline is excreted in the urine and faeces as unchanged drug. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces. The terminal half-life after a single 20 mg doxycycline dose averaged 18h.
Special populations:
The half-life is not significantly altered in patients with severely impaired renal function. Doxycycline is not eliminated to any great extent during haemodialysis.
The effect of doxycycline on the ability to drive or operate heavy machinery has not been studied. There is no evidence to suggest that doxycycline may affect these abilities.
The effect of Tetradox on the ability to drive or operate heavy machinery has not been studied. There is no evidence to suggest that Tetradox may affect these abilities.
Tetradox therapy has been associated with nausea and dizziness. Those affected should not drive or operate machinery.
No special requirements.
